Abstract
Cachexia is a complex wasting syndrome that overwhelmingly affects the majority of late-stage cancer patients. Additionally, there are currently no efficacious therapeutic agents to treat the muscle atrophy induced by the cancer. While several preclinical studies have investigated the molecular signals orchestrating cachexia, very little information exists pertaining to ovarian cancer and the associated cachexia. Work from our lab has recently demonstrated that the steroidal lactone Withaferin A (WFA) is capable of attenuating the atrophying effects of ovarian cancer in a preclinical mouse model. However, it remained to be determined whether WFA’s effect was in response to its anti-tumorigenic properties, or if it was capable of targeting skeletal muscle directly. The purpose of this study was to uncover whether WFA was capable of regulating muscle mass under tumor-free and tumor-bearing conditions. Treatment with WFA led to an improvement in functional muscle strength and mass under tumor-bearing and naïve conditions. WFA and ovarian cancer were observed to act antagonistically upon critical skeletal muscle regulatory systems, notably myogenic progenitors and proteolytic degradation pathways. Our results demonstrated for the first time that, while WFA has anti-tumorigenic properties, it also exerts hypertrophying effects on skeletal muscle mass, suggesting that it could be an anti-cachectic agent in the settings of ovarian cancer.
Highlights
Late-stage cancer patients frequently exhibit the complex metabolic syndrome cachexia (Gadducci et al, 2001)
We attempted to elucidate whether Withaferin A (WFA) has an effect on functional muscle strength and the size of muscle in tumorfree mice, and to corroborate our prior results in tumorbearing mice using the same lower dosage of WFA (2 mg/kg), but a different upper dosage of WFA (4 mg/kg) due to the deleterious effects previously observed with 6 mg/kg of WFA
Before the mice received i.p. xenografts of the A2780 ovarian cancer cells, we performed forelimb and total grip strength analyses to ensure no significant differences within the groups stratified to become tumor-free or tumor-bearing existed at the start of the study (Supplementary Figures 1A,B)
Summary
Late-stage cancer patients frequently exhibit the complex metabolic syndrome cachexia (Gadducci et al, 2001). Cachexia is primarily marked by a loss of muscle strength and mass (Fearon et al, 2011; Fearon et al, 2012). This sequela of cancer is observed in up to 80% of cancer patients and is the direct cause of mortality in up to 30% of cancer patients, contingent upon the oncological setting (Fearon et al, 2011; Fearon et al, 2012). A recent meta-analysis reported that cachexia is observed in 11–54% of ovarian cancer patients, it was noted that this wide range could be attributable to different cut-off points for assessing the induction of sarcopenia in patients (Ubachs et al, 2019)
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